This invention relates to orgotein derivatives.
Orgotein is the non-proprietary name assigned by the United States Adopted Name Council to members of a family of water-soluble protein congeners in substantially pure, injectable form, i.e., substantially free from other proteins which are admixed or associated therewith in the sources thereof. U.S. Pat. No. 3,758,682 claims pharmaceutical compositions orgotein. Various uses of orgotein are claimed in U.S. Pat. No. 3,637,441; 3,773,928; 3,773,929; and 3,781,414.
The orgotein metalloproteins are members of a family of protein congeners having a characteristic combination of physical, chemical, biological and pharmacodynamic properties. Each of these congeners is characterized physically by being the isolated, substantially pure form of a globular, buffer and water-soluble protein having a highly compact native conformation which, although heat labile, is stable to heating for several minutes at 65.degree. C. at pH 4-10. Chemically, each is characterized by containing all but 0-2 of the protein aminoacids, a small percentage of carbohydrate, no lipids, 0.1 to 1.0% metal content provided by one to 5 gram atoms per mole of one or more chelated divalent metals having an ionic radius of 0.60 to 1.00 A., and substantially no chelated monovalent metals or those that are cell poisons in the molecule.
In 1969, the bovine congeners of the orgotein protein was discovered to be an enzyme which has the ability to catalyze the destruction of superoxide radicals in a disproportionation into molecular oxygen and hydrogen peroxide. The name superoxide dismutase (SOD) was assigned to the protein on the basis of this enzymatic activity by McCord, J. M. and Fridovich, I., J. Biol. Chem. 244, 6049-6055 (1969).
Studies with .sup.99M Tc labeled orgotein established that orgotein remains only briefly in the blood after intravenous administration. For example, within 15 minutes after intravenous administration of the labeled orgotein, virtually all radioactivity was found concentrated in the kidneys. A similar although less dramatic pooling of the orgotein in the kidneys also occurs after subcutaneous injection. In clinical situations where a plurality of injections of orgotein is desirable, e.g., rheumatoid arthritis and other chronic inflammatory conditions, it is desirable to maintain the orgotein in the body fluids for as long as possible.
It has now been found that orgotein cross-linked with itself or with serum or tissue protein has a much longer, e.g. 3-10 times, serum half-life than orgotein itself.